INDICATIONS AND USAGE

SUBLOCADE™ (buprenorphine extended-release) is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

SUBLOCADE was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial in treatment-seeking patients, who met the DSM-V criteria for moderate or severe opioid use disorder1

The safety of SUBLOCADE was evaluated in 848 opioid-dependent patients1

The primary endpoint was the cumulative distribution function (CDF) of the percentage of urine samples negative for illicit opioids combined with self‐reports negative for illicit opioid use collected from Week 5 through Week 241,3

After SUBLOCADE injection, an initial buprenorphine peak was observed and the median Tmax occurred at 24 hours after injection1

After the initial buprenorphine peak, the plasma buprenorphine concentrations decreased slowly to a plateau1

The observed plateau for maximal response was reached at buprenorphine plasma concentrations of approximately 2-3 ng/mL for illicit opioid use1

Exposure-response Relationship for Illicit Opioid Use1,3‡

‡Exposure-response relationship for illicit opioid use was assessed using pooled data from the 300:100 mg and 300:300 mg arms.3

Exposure-response relationships were assessed for illicit opioid use based on urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use, using data obtained from 489 opioid‑dependent patients in the double-blind Phase 3 study1

In addition to study medication, all subjects received manual-guided psychosocial support at least once a week1

The primary objective of the study was to demonstrate that following the 300 mg subcutaneous (SC) injection of SUBLOCADE, the drug liking for 6 mg or 18 mg of a hydromorphone challenge was noninferior (ie, shown to be not substantially more likable) to the drug liking of a placebo challenge as measured by a 100-point visual analog scale (VAS)1,3

VAS is a 100-mm scale anchored by "none" moving to "extremely" modified to measure reports of "drug liking" and "high"3

Patients who met Diagnostic and Statistical Manual of Mental Disorders (DSM-5®) criteria for moderate or severe OUD at screening, who were not seeking treatment, were inducted and stabilized on transmucosal buprenorphine to reach a final dose between 8 mg/day-24 mg/day3

Patients received 300 mg of SUBLOCADE on Day 1 (N=39) and Day 29 (N=30)3

A hydromorphone and placebo challenge was administered during transmucosal buprenorphine induction and then every week following each injection of SUBLOCADE and for 8 weeks after the second and last injection3

Patients were challenged with either hydromorphone or placebo on Days 5-7 of each week. The order of hydromorphone and placebo was randomized and patients received 1 challenge per day3

All 12 weeks of the treatment period demonstrated blockade for both 6 mg and 18 mg hydromorphone following the second SUBLOCADE injection1

Wide variation can be seen in isolated measurements from individual patients, shown in the figure below1

The study was not designed, nor intended, to draw any head-to-head comparisons between transmucosal buprenorphine and SUBLOCADE 3

Patients were challenged with both doses of hydromorphone and placebo at baseline, during the week they were stabilized on TM BUP, and during each of the 12 weeks of study for 3 consecutive days (each week on days 5-7) in a randomized fashion3

VAS measurements of drug-liking were assessed before and after these challenges

Complete blockade continued throughout the 8 weeks of observation that followed the second SUBLOCADE injection1

In some cases, 95% confidence intervals (CIs) are not visible, as the median was equal to the confidence limit. The horizontal line at 20 mm delineates the non-inferiority margin for opioid blockade. Next to median estimates, individual data are summarized by circles, the area of which is proportional to the number of patients at that location1

Beneath that treatment week indicator is the number of patients (N) who provided those VAS measurements for all 3 challenges with placebo, 6 mg hydromorphone, and 18 mg hydromorphone1

PHASE 3 TRIAL

Efficacy and safety of SUBLOCADE were evaluated in a randomized, double‑blind, placebo‑controlled, multicenter trial1

Study Design1,3

§IDC=individualized drug counseling (manual-guided psychosocial support at least once a week).

Induction and Stabilization

Following screening, there was a 3-day induction period during which patients received 2 mg to 24 mg of TM BUP, which was then followed by a stabilization period lasting from 4 to 11 days, during which patients received 8 mg to 24 mg of TM BUP1,3

Primary Endpoint

The cumulative distribution function (CDF) of the percentage of urine samples negative for illicit opioids combined with self-reports negative for illicit opioid use collected from Week 5 to 241,3

For various percentages of opioid-free weeks, the table shows the fraction of patients achieving that criterion. The table is cumulative, so that a patient whose percent of opioid-free weeks is, for example, 50%, is also included at every level of opioid-free week percentage below 50%. Missing values and values after premature discontinuation were considered positive1

Safety

SUBLOCADE safety was evaluated in 848 opioid-dependent patients1

The systemic safety profile for SUBLOCADE was consistent with the known safety profile of transmucosal buprenorphine (TM BUP)1¶

TEAEs that led to discontinuation of SUBLOCADE were reported in a similar percentage of patients in the 300:300 mg and the 300:100 mg groups compared with the placebo group (5.0% and 3.4% vs 2.0%, respectively)3

Dose-dependent hepatic effects observed in the Phase 3, double-blind study included the incidence of alanine aminotransferase (ALT) more than 3 times the upper limit of normal (>3 x ULN) in 12.4%, 5.4%, and 4.0% of the SUBLOCADE 300:300 mg, 300:100 mg, and placebo groups, respectively. The incidence of aspartate aminotransferase (AST) >3 x ULN was 11.4%, 7.9%, and 1.0%, respectively1

¶SUBLOCADE was given by a healthcare provider in clinical trials.1

Injection site reactions reported for SUBLOCADE1

Injection Site Adverse Drug Reactions Reported by ≥2% of Patients in the Phase 3 Double-blind Study1

Most injection site-related adverse events were of mild to moderate severity, with the exception of 1 report of severe injection site pruritus1

Injection site adverse drug reactions in ≥2% of patients in the Phase 3 trial, including roll-over study, were induration, bruising, swelling, discomfort, reaction, cellulitis, and infection1

There were no serious injection site reactions. One reaction, an injection site ulcer, led to study treatment discontinuation1

Longer-term experience for SUBLOCADE

In an interim analysis of the ongoing open-label long-term safety study, safety was evaluated for up to 12 injections over the course of a year1

The overall adverse event profile in the long-term safety study was similar to the double-blind trial1

Adverse events were reported for 432 of 669 patients during the treatment period1

HOW SUBLOCADE WORKS

Clinical development and study results for SUBLOCADE

Addictive effects of opioids are mediated by the μORs, making them a target of interest in treating OUD4

SUBLOCADE is a once-monthly injection for moderate to severe OUD. Watch the video to learn more1

IMPORTANT SAFETY INFORMATION AND BOXED WARNING

INDICATIONS AND USAGE

WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; SUBLOCADE RISK EVALUATION AND MITIGATION STRATEGY

Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously

Because of the risk of serious harm or death that could result from intravenous self-administration, SUBLOCADE is only available through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense SUBLOCADE must be certified in this program and comply with the REMS requirements

SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

Prescription use of this product is limited under the Drug Addiction Treatment Act.

CONTRAINDICATIONS: SUBLOCADE should not be administered to patients who are hypersensitive to buprenorphine or any component of the ATRIGEL® delivery system.

WARNINGS AND PRECAUTIONS

Addiction, Abuse, and Misuse: SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors.

Risk of Respiratory Depression and Concomitant Use of Benzodiazepines or Other CNS Depressants with Buprenorphine: Buprenorphine has been associated with life‐threatening respiratory depression, overdose, and death, particularly when misused by self-injection or with concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines, other CNS depressants, opioid analgesics, and alcohol while under treatment with SUBLOCADE. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider.

Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. Newborns should be observed for signs of NOWS and managed accordingly. Advise pregnant women receiving opioid addiction treatment with SUBLOCADE of the risk of neonatal opioid withdrawal syndrome.

Adrenal Insufficiency: Adrenal insufficiency has been reported with opioid use. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off the opioid.

Discontinuation of SUBLOCADE Treatment: Due to the long-acting nature of SUBLOCADE, if treatment is discontinued, monitor patients for several months for withdrawal and treat appropriately.

Inform patients that they may have detectable levels of buprenorphine for a prolonged period of time after treatment with SUBLOCADE. Considerations of drug-drug interactions, buprenorphine effects, and analgesia may continue to be relevant for several months after the last injection.

Risk of Hepatitis, Hepatic Events: Because cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine, monitor liver function tests prior to treatment and monthly during treatment.

Hypersensitivity Reactions: Hypersensitivity to buprenorphine-containing products have been reported most commonly as rashes, hives, and pruritus. Some cases of bronchospasm, angioneurotic edema, and anaphylactic shock have also been reported.

Precipitation of Opioid Withdrawal in Patients Dependent on Full Agonist Opioids: Buprenorphine may precipitate opioid withdrawal signs and symptoms in persons who are currently physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. Verify that patients have tolerated and are dose adjusted on transmucosal buprenorphine before subcutaneously injecting SUBLOCADE.

Risks Associated With Treatment of Emergent Acute Pain: When patients need acute pain management, or may require anesthesia, treat patients receiving SUBLOCADE currently or within the last 6 months with a non-opioid analgesic whenever possible. If opioid therapy is required, patients may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function, as higher doses may be required for analgesic effect and therefore, a higher potential for toxicity exists with opioid administration.

Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with SUBLOCADE.

Use in Opioid Naïve Patients: Because death has been reported for opioid naïve individuals who received buprenorphine sublingual tablet, SUBLOCADE is not appropriate for use in opioid naïve patients.

Use in Patients With Impaired Hepatic Function: Because buprenorphine levels cannot be rapidly decreased, SUBLOCADE is not recommended for patients with pre-existing moderate to severe hepatic impairment. Patients who develop moderate to severe hepatic impairment while being treated with SUBLOCADE should be monitored for several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Use in Patients at Risk for Arrhythmia: Buprenorphine has been observed to prolong the QTc interval in some patients participating in clinical trials. Avoid use of buprenorphine in patients with a history of Long QT Syndrome or an immediate family member with this condition or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval.

Impairment of Ability to Drive or Operate Machinery: SUBLOCADE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Caution patients about driving or operating hazardous machinery until they are reasonably certain that SUBLOCADE does not adversely affect their ability to engage in such activities.

Elevation of Cerebrospinal Fluid Pressure: Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Elevation of Intracholedochal Pressure: Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Effects in Acute Abdominal Conditions: Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Unintentional Pediatric Exposure: Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

ADVERSE REACTIONS: Adverse reactions commonly associated with SUBLOCADE (≥5% of subjects) during clinical trials were constipation, headache, nausea, vomiting, increased hepatic enzymes, fatigue, and injection site pain and pruritus. This is not a complete list of potential adverse events. Please see the full Prescribing Information for a complete list.

DRUG INTERACTIONS

Serotonergic Drugs: If concomitant use with serotonergic drugs is warranted, monitor for serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug.

Consult the full Prescribing Information for SUBLOCADE for more information on potentially significant drug interactions.

To report pregnancy or side effects associated with taking SUBLOCADE, please call 1-877-782-6966.

INDICATIONS AND USAGE

SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

Indivior Inc. (Indivior) is required to disclose the following requirements for participation and use to all participants. This free service provides a list of physicians, nurse practitioners, and physician assistants (hereafter collectively and individually referred to as HCP(s) or Healthcare Providers) who are waivered per the Drug Addiction Treatment Act of 2000 (DATA 2000) and the Comprehensive Addiction and Recovery Act of 2016 to treat opioid dependence with FDA-approved medications and who have agreed to be in the Indivior Treatment Locator (Locator).

The maximum number of patients that an HCP may treat is limited by law; therefore, some HCPs may not always be able to accept new patients.

Participating HCPs do not pay a fee to be listed in the Locator, and their participation does not impose any requirements on the manner in which they treat or provide services to patients.

Participating HCPs are chosen for your search based on the geographical search information entered.

Some of the participating HCPs may be consultants to Indivior and receive payment for services. Some may have other financial relationships with Indivior as recipients of research grants, or other similar payments, or they may have an ownership interest in Indivior.

HCPs may request to be removed from the Locator and Indivior retains the right to remove HCPs from the Locator for the following reasons:

The HCP's contact information is no longer valid;

The HCP's DATA 2000 waiver or medical license, healthcare provider license, or state prescribing license is suspended, revoked, or restricted;

The HCP is not in compliance with DATA 2000 and its implementing regulations; or

The company has information or determines after investigation that the HCP may be engaging in the unsafe prescription of our products

Limitation of Indivior Liabilities

Indivior does not warrant, whether expressed or implied, that the Locator is accurate or complete. Indivior does not recommend or endorse any HCP included in the Locator for any purpose, nor is the Locator a tool to verify a specific HCP's credentials or qualifications. It is your responsibility to select an HCP appropriate for your needs and you assume full responsibility for your interactions with any HCP you contact through the Locator. Indivior is not responsible for the medical care or advice given by any participating HCP you choose to contact.

Do you acknowledge that you understand how the Locator works and that you'd like to continue to your results?

COMING SOON

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IMPORTANT SAFETY INFORMATION AND BOXED WARNING

INDICATIONS AND USAGE

WARNING: RISK OF SERIOUS HARM OR DEATH WITH INTRAVENOUS ADMINISTRATION; SUBLOCADE RISK EVALUATION AND MITIGATION STRATEGY

Serious harm or death could result if administered intravenously. SUBLOCADE forms a solid mass upon contact with body fluids and may cause occlusion, local tissue damage, and thrombo-embolic events, including life threatening pulmonary emboli, if administered intravenously

Because of the risk of serious harm or death that could result from intravenous self-administration, SUBLOCADE is only available through a restricted program called the SUBLOCADE REMS Program. Healthcare settings and pharmacies that order and dispense SUBLOCADE must be certified in this program and comply with the REMS requirements

SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

Prescription use of this product is limited under the Drug Addiction Treatment Act.

CONTRAINDICATIONS: SUBLOCADE should not be administered to patients who are hypersensitive to buprenorphine or any component of the ATRIGEL® delivery system.

WARNINGS AND PRECAUTIONS

Addiction, Abuse, and Misuse: SUBLOCADE contains buprenorphine, a Schedule III controlled substance that can be abused in a manner similar to other opioids. Buprenorphine is sought by people with opioid use disorder and is subject to criminal diversion. Monitor patients for conditions indicative of diversion or progression of opioid dependence and addictive behaviors.

Risk of Respiratory Depression and Concomitant Use of Benzodiazepines or Other CNS Depressants with Buprenorphine: Buprenorphine has been associated with life‐threatening respiratory depression, overdose, and death, particularly when misused by self-injection or with concomitant use of benzodiazepines or other CNS depressants, including alcohol. Warn patients of the potential danger of self-administration of benzodiazepines, other CNS depressants, opioid analgesics, and alcohol while under treatment with SUBLOCADE. Counsel patients that such medications should not be used concomitantly unless supervised by a healthcare provider.

Neonatal Opioid Withdrawal Syndrome: Neonatal opioid withdrawal syndrome (NOWS) is an expected and treatable outcome of prolonged use of opioids during pregnancy. NOWS may be life-threatening if not recognized and treated in the neonate. Newborns should be observed for signs of NOWS and managed accordingly. Advise pregnant women receiving opioid addiction treatment with SUBLOCADE of the risk of neonatal opioid withdrawal syndrome.

Adrenal Insufficiency: Adrenal insufficiency has been reported with opioid use. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off the opioid.

Discontinuation of SUBLOCADE Treatment: Due to the long-acting nature of SUBLOCADE, if treatment is discontinued, monitor patients for several months for withdrawal and treat appropriately.

Inform patients that they may have detectable levels of buprenorphine for a prolonged period of time after treatment with SUBLOCADE. Considerations of drug-drug interactions, buprenorphine effects, and analgesia may continue to be relevant for several months after the last injection.

Risk of Hepatitis, Hepatic Events: Because cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine, monitor liver function tests prior to treatment and monthly during treatment.

Hypersensitivity Reactions: Hypersensitivity to buprenorphine-containing products have been reported most commonly as rashes, hives, and pruritus. Some cases of bronchospasm, angioneurotic edema, and anaphylactic shock have also been reported.

Precipitation of Opioid Withdrawal in Patients Dependent on Full Agonist Opioids: Buprenorphine may precipitate opioid withdrawal signs and symptoms in persons who are currently physically dependent on full opioid agonists such as heroin, morphine, or methadone before the effects of the full opioid agonist have subsided. Verify that patients have tolerated and are dose adjusted on transmucosal buprenorphine before subcutaneously injecting SUBLOCADE.

Risks Associated With Treatment of Emergent Acute Pain: When patients need acute pain management, or may require anesthesia, treat patients receiving SUBLOCADE currently or within the last 6 months with a non-opioid analgesic whenever possible. If opioid therapy is required, patients may be treated with a high-affinity full opioid analgesic under the supervision of a physician, with particular attention to respiratory function, as higher doses may be required for analgesic effect and therefore, a higher potential for toxicity exists with opioid administration.

Advise patients of the importance of instructing their family members, in the event of emergency, to inform the treating healthcare provider or emergency room staff that the patient is physically dependent on an opioid and that the patient is being treated with SUBLOCADE.

Use in Opioid Naïve Patients: Because death has been reported for opioid naïve individuals who received buprenorphine sublingual tablet, SUBLOCADE is not appropriate for use in opioid naïve patients.

Use in Patients With Impaired Hepatic Function: Because buprenorphine levels cannot be rapidly decreased, SUBLOCADE is not recommended for patients with pre-existing moderate to severe hepatic impairment. Patients who develop moderate to severe hepatic impairment while being treated with SUBLOCADE should be monitored for several months for signs and symptoms of toxicity or overdose caused by increased levels of buprenorphine.

Use in Patients at Risk for Arrhythmia: Buprenorphine has been observed to prolong the QTc interval in some patients participating in clinical trials. Avoid use of buprenorphine in patients with a history of Long QT Syndrome or an immediate family member with this condition or those taking Class IA antiarrhythmic medications (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic medications (e.g., sotalol, amiodarone, dofetilide), or other medications that prolong the QT interval.

Impairment of Ability to Drive or Operate Machinery: SUBLOCADE may impair the mental or physical abilities required for the performance of potentially dangerous tasks such as driving a car or operating machinery. Caution patients about driving or operating hazardous machinery until they are reasonably certain that SUBLOCADE does not adversely affect their ability to engage in such activities.

Elevation of Cerebrospinal Fluid Pressure: Buprenorphine may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation.

Elevation of Intracholedochal Pressure: Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract.

Effects in Acute Abdominal Conditions: Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Unintentional Pediatric Exposure: Buprenorphine can cause severe, possibly fatal, respiratory depression in children who are accidentally exposed to it.

ADVERSE REACTIONS: Adverse reactions commonly associated with SUBLOCADE (≥5% of subjects) during clinical trials were constipation, headache, nausea, vomiting, increased hepatic enzymes, fatigue, and injection site pain and pruritus. This is not a complete list of potential adverse events. Please see the full Prescribing Information for a complete list.

DRUG INTERACTIONS

Serotonergic Drugs: If concomitant use with serotonergic drugs is warranted, monitor for serotonin syndrome, particularly during treatment initiation, and during dose adjustment of the serotonergic drug.

Consult the full Prescribing Information for SUBLOCADE for more information on potentially significant drug interactions.

To report pregnancy or side effects associated with taking SUBLOCADE, please call 1-877-782-6966.

INDICATIONS AND USAGE

SUBLOCADE is indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a transmucosal buprenorphine-containing product, followed by dose adjustment for a minimum of 7 days.

SUBLOCADE should be used as part of a complete treatment plan that includes counseling and psychosocial support.

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